Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

Standard Venipuncture vs a Capillary Blood Collection Device for the Prospective Determination of Abnormal Liver Chemistry.

BACKGROUND: Abnormal liver function is a common manifestation of human disease and may also occur in approved and investigational medications as drug-induced liver injury (DILI). Capillary blood collection devices may allow for more frequent and convenient measurement outside of the clinic. Validation of such approaches is lacking. METHODS: This prospective, biospecimens collection study evaluated the Tasso+ in patients with abnormal liver tests (NCT05259618). The primary objective was to define the concordance of alanine aminotransferase (ALT) obtained via Tasso+ compared to standard venipuncture. Secondary objectives included measurement of 14 other analytes and patient surveys. At the time of venipuncture, 2 Tasso+ samples were collected: one was centrifuged and shipped, and the other was refrigerated and shipped as whole blood. RESULTS: Thirty-six patients with elevated ALT values were enrolled. In total, 100 venipuncture, 50 Tasso+ centrifuged, and 48 Tasso+ whole blood samples were obtained. Tasso+ centrifuged samples demonstrated concordance correlation coefficients (CCC) of >0.99 for ALT, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin and CCC >0.95 for albumin, chloride, enzymatic creatinine, serum glucose, magnesium, and phosphorus. Tasso+ whole blood showed CCC of >0.99 for AST, bilirubin total, and enzymatic creatinine and CCC >0.95 for ALT, ALP, albumin, magnesium, and phosphorus. Hemolysis was comparable across the 3 sample types, but its impact was reflected in the Tasso+ potassium data. Patient feedback indicated a very favorable patient experience. CONCLUSIONS: The capillary blood collection device, Tasso+, showed substantial to almost perfect concordance to standard venipuncture for measurement of abnormal liver function. Studies are ongoing to validate longitudinal sampling outside of the clinic. Clinicaltrials.gov Registration Number: NCT05259618.

Drug-induced liver injury and drug development: industry perspective.

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

How to avoid being surprised by hepatotoxicity at the final stages of drug development and approval.

Drugs that caused severe drug-induced live injury (DILI) in humans have typically not shown clear hepatotoxic signals in preclinical assessment. However, clinical trial databases may show evidence of a drug's potential for severe DILI if clinical and laboratory data are evaluated for evidence of milder liver injury. The most specific indicator during a clinical trial for a drug's potential to cause severe DILI is occurrence of cases of drug induced hepatocellular injury accompanied by altered liver function (eg, elevated direct bilirubin). Meticulous causality assessment of hepatic cases and strict adherence to hepatic discontinuation rules are critical components of this approach.

Comparison of seven liver allocation models with respect to lives saved among patients on the liver transplant waiting list.

The patients with end-stage liver disease (ESLD) on the liver transplant waiting list are prioritized for transplant based on the model for end-stage liver disease (MELD) score. We developed and used an innovative approach to compare MELD to six proposed alternatives with respect to waiting list mortality. Our analysis was based on United Network for Organ Sharing data of patients with ESLD on the waiting list between January 2006 and June 2009. We compared six allocation models to MELD. Two models were based on reweighting the variables used by MELD: an "updated" MELD, and ReFit MELD. Four models also included serum sodium: MESO, MeldNa, UKELD, and ReFit MELDNa. We estimated that UKELD and the updated MELD would result in significantly fewer lives saved. There were no significant differences between the other models. Our new approach can supplement standard methods to provide insight into the relative performance of liver allocation models in reducing waiting list mortality. Our analysis suggests that UKELD and the updated MELD score would not be optimal for reducing waiting list mortality in the United States.